Optimizing asparaginyl tRNA synthetase docking with quinoxalines.
Journal name: World Journal of Pharmaceutical Research
Original article title: Application of computational strategies for optimization of asparginyl t-rna synthetase docking study of quinoxalines
The WJPR includes peer-reviewed publications such as scientific research papers, reports, review articles, company news, thesis reports and case studies in areas of Biology, Pharmaceutical industries and Chemical technology while incorporating ancient fields of knowledge such combining Ayurveda with scientific data.
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Summary of article contents:
Introduction
The study explores the potential use of asparginyl t-RNA synthetase inhibitors as antifilarial agents, particularly for the treatment of filariasis. The research involves the synthesis of a series of diphenyl quinoxaline derivatives and the use of molecular docking studies to evaluate how these compounds bind to the enzyme asparginyl t-RNA synthetase (PDB: 2kqr). The results demonstrate a correlation between the enzyme inhibitory activity and the binding affinities of the docked ligands, highlighting the therapeutic potential of these novel quinoxaline derivatives.
Molecular Docking Studies
Molecular docking simulations were performed using the software V-Life MDS 4.5, which evaluates the best conformations of synthesized compounds within the active site of asparginyl t-RNA synthetase. The methodology involved preparing the target protein by removing water molecules and optimizing the ligand structures. The effective docking process allowed for the analysis of binding interactions, where the calculated binding energies indicated strong associations between the synthesized compounds and the target enzyme. This computational approach is crucial in understanding the binding modes and interaction energetics of the newly synthesized quinoxaline derivatives.
Synthesis of Quinoxaline Derivatives
The synthesis of substituted sulfonamido quinoxalines was achieved using 2,3-diphenylquinoxaline-6-sulfonylchloride as an intermediate, which was produced through refluxing with chlorosulfonic acid. Different organic amines were reacted under various conditions to yield a range of 6-sulfonamido derivatives. Following synthesis, these compounds were subjected to molecular docking studies with the parasite Brugia malayi asparginyl t-RNA synthetase. The docking results reflected promising negative scores, correlating well with the biological activity of the synthesized derivatives.
ADME and Toxicity Predictions
The study emphasizes the importance of analyzing ADME (Absorption, Distribution, Metabolism, and Excretion) properties and toxicity profiles early in drug discovery to identify viable drug candidates. Using the PreMetabo software, the synthesized compounds were screened for their drug-likeness and non-toxic characteristics. The results indicated that the selected compounds demonstrated favorable ADME properties, adhering to Lipinski's Rule of Five, thus enhancing their potential as drug candidates targeting filariasis.
Conclusion
The research presents a comprehensive analysis of quinoxaline derivatives as potential antifilarial agents through molecular docking studies and ADME-T evaluations. The derivative R6 exhibited the best docking score and exhibited good biological activity in in vitro studies. The findings affirm the binding affinity of these compounds to the asparginyl t-RNA synthetase receptor, suggesting that these quinoxaline analogues could be further developed into effective treatments against Brugia malayi. The methodology outlined paves the way for future drug design efforts based on the optimized lead compounds derived from this study.
Original source:
This page is merely a summary which is automatically generated hence you should visit the source to read the original article which includes the author, publication date, notes and references.
Rahul Ingle, Shailesh Wadher and Gajanan Sonwane
World Journal of Pharmaceutical Research:
(An ISO 9001:2015 Certified International Journal)
Full text available for: Application of computational strategies for optimization of asparginyl t-rna synthetase docking study of quinoxalines
Source type: An International Peer Reviewed Journal for Pharmaceutical and Medical and Scientific Research
Doi: 10.20959/wjpr201710-9383
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FAQ section (important questions/answers):
What is the focus of the research on quinoxalines?
The research focuses on the potential use of asparginyl t-RNA synthetase inhibitors, specifically quinoxalines, as antifilarial agents for treating filariasis.
What role do molecular docking studies play in this research?
Molecular docking studies evaluate the binding affinities of synthesized quinoxaline derivatives with asparginyl t-RNA synthetase, helping to predict their inhibitory activity against the enzyme.
What software was used for the docking studies?
The docking studies were conducted using V-Life MDS 4.5 software, which is considered accurate for calculating interaction energies between ligands and macromolecular systems.
What was the outcome of the docking studies?
The docking studies revealed that compound R6 exhibited the best docking score and showed promising interactions with the asparginyl t-RNA synthetase enzyme.
How were the ADME properties evaluated?
ADME properties were evaluated using the PreMetabo software to filter compounds based on their drug-likeness and non-toxic profiles, ensuring suitable candidates for development.
What is the significance of the findings?
The findings indicate that the synthesized quinoxaline derivatives, particularly R6, possess strong binding affinity towards the target enzyme, and have potential as drug candidates against Brugia malayi.
Glossary definitions and references:
Scientific and Ayurvedic Glossary list for “Optimizing asparaginyl tRNA synthetase docking with quinoxalines.”. This list explains important keywords that occur in this article and links it to the glossary for a better understanding of that concept in the context of Ayurveda and other topics.
1) Table:
Table in this context refers to a structured representation of data or results derived from experiments or analyses. It often summarizes findings like binding interactions, docking scores, and various parameters relevant to the compounds studied. Tables facilitate easier comparison and clearer understanding of complex data sets, enhancing the communication of scientific results.
2) Life:
Life in this text relates to the V-Life software used for molecular docking studies. This computational tool plays a critical role in simulating the interaction between ligands (drugs) and macromolecules (proteins). It aids researchers in assessing the binding affinities and interactions, thus streamlining the drug discovery process.
3) Field:
Field, in this case, refers to a scientific domain or specialized area of study. The text discusses the use of force fields, which are mathematical models used in computational chemistry for predicting molecular interactions. Understanding fields is essential for simulating and optimizing compound behaviors in biological systems.
4) Drug:
Drug pertains to the synthesized compounds being studied for therapeutic purposes. In this context, asparginyl t-RNA synthetase inhibitors derived from quinoxalines are being investigated as potential antifilarial agents. The effectiveness of these candidate drugs is evaluated through docking studies and biological activity assessments.
5) Toxicity:
Toxicity refers to the harmful effects of substances on living organisms. The assessment of toxicity is crucial in drug development, as it helps to identify compounds that are safe for human use. The text emphasizes toxicity screening of synthesized compounds to eliminate harmful candidates early in the drug discovery process.
6) Water:
Water is mentioned in the context of solubility testing of the synthesized compounds. The ability of a drug to dissolve in water is a key factor affecting its bioavailability and pharmacokinetics. The text outlines that solubility studies help determine the potential efficacy of the compounds when administered to patients.
7) Study (Studying):
Study refers to the systematic investigation conducted to understand the binding interactions of quinoxaline derivatives with the enzyme asparginyl t-RNA synthetase. The process involves molecular docking, synthesis, and analysis of various parameters, highlighting the importance of structured research methodologies in uncovering new therapeutic agents.
8) Calculation:
Calculation refers to the quantitative assessment of various interactions, energies, and binding scores during the docking studies. Precise calculations are fundamental to determining how effectively the compounds interact with the target enzyme, thereby informing subsequent drug design and optimization efforts based on numerical data.
9) Activity:
Activity denotes the biological efficacy of the synthesized compounds against specific targets like asparginyl t-RNA synthetase. The level of activity is correlated with binding affinities obtained through molecular docking studies, giving insight into which compounds could be developed as effective drug candidates against parasitic infections.
10) Blood:
Blood in this context refers to the biological fluid that carries oxygen and nutrients through the body, as well as its role in drug distribution. Understanding a compound's ability to cross the blood-brain barrier, as mentioned in the ADME profile, is essential for predicting its central nervous system effects.
11) Evolution:
Evolution here relates to the changes and adaptations in molecular docking methodologies used over time. The development of advanced algorithms and computational techniques has significantly enhanced the accuracy of predicting interactions between drugs and their biological targets, thus optimizing the drug discovery process.
12) Surface:
Surface refers to the molecular surface area interactions that can influence binding events between drugs and targets. In drug design, understanding the surface properties helps in predicting how well compounds can interact with proteins and their accessibility to active sites on target enzymes.
13) India:
India denotes the location where the research was conducted, specifically at the School of Pharmacy, S.R.T.M. University. The geographical context highlights the collaboration among Indian educational institutions in advancing pharmaceutical research and development, emphasizing the country's role in global health solutions.
14) Discussion:
Discussion in this context pertains to the section of research that interprets the results obtained from experiments. It involves a critical analysis of data, comparing docking scores, and evaluating the implications of findings to support further research directions and potential therapeutic applications.
15) Antibiotic (Antibacterial):
Antibiotic indicates the class of compounds under investigation. Although primarily known for targeting bacterial infections, the text explores the potential of quinoxalines as inhibitors for parasites. The concept of antibiotic activities expands the scope of drug applications beyond traditional uses, highlighting innovative therapeutic strategies.
16) Reason:
Reason refers to the justification provided for conducting the study. It underlines the necessity to explore new compounds that possess antifilarial properties. The implications of the study go beyond scientific interest; they aim to address health challenges caused by parasitic infections in humans.
17) Shasha (Sasa, Shasa, Sasha):
SASA, or solvent-accessible surface area, is a physicochemical descriptor used in evaluating the properties of compounds. It provides insights into how well a molecule interacts with solvent, which is crucial for understanding solubility, stability, and overall pharmacokinetics of the synthesized compounds during drug development.
18) Pose:
Pose refers to the specific orientation and conformation of a ligand when it binds to a protein during molecular docking. The quality of different poses can dictate the success of drug-target interactions, emphasizing the importance of exploring various binding modes to optimize lead compounds.
19) Wall:
Wall in this context refers to the van der Waals interactions, which play a significant role in molecular docking. These interactions influence the stability of the ligand-receptor complex and are critical for calculating interaction energies, further informing the binding behavior of potential drug candidates.
20) Pur:
Poor relates to inadequate outcomes or characteristics, specifically in the context of drug candidates failing in trials. The study aims to evaluate and filter candidates based on ADME properties to minimize instances of poor absorption, distribution, metabolism, and excretion, ultimately enhancing the likelihood of successful therapeutic agents.